Immediately upon a sterile birth, mammals assemble complex bacterial communities on almost all environmentally exposed surfaces (called the microbiota). Though it has been appreciated for decades that humans harbor multitudes of commensal bacteria, recent studies have begun to reveal the extraordinary diversity and complexity of our microbial ecosystems. The NIH funded Human Microbiome Project aims to define the bacterial fingerprint of humans in health and disease by cataloging DNA sequences of the microbiota. However, molecular mechanism(s) employed by commensal bacteria to mediate persistence in the gut remain almost entirely unknown. Bacteroides are one of the most numerically prominent and biologically important genera in the human microbiota. How these (or any other group of) bacteria stably colonize the mammalian gut is unknown. To understand the dynamics of host-microbiota associations in the gut, we developed a functional in vivo approach to identify mechanisms that mediate intestinal colonization. We identified a locus that encodes for a novel set of genes that are highly conserved in many sequenced intestinal Bacteroides. Most importantly, deletion of the genes abolishes stable colonization by Bacteroides. Collectively, our innovative findings strongly suggested we have uncovered a novel and evolutionarily conserved system for persistent gut colonization by the Bacteroides. Our overarching hypothesis is that a defined molecular mechanism mediates the dynamics of microbial ecology within the mammalian intestine. PUBLIC HEALTH RELEVANCE: The importance of the microbiota to vital biological processes in humans is indisputable, and changes in the microbiota are associated with numerous diseases. This project will examine the molecular mechanisms by which an important class of human commensal bacteria establish and maintain long-term gut colonization. A molecular understanding for how complex microbiotas are shaped during health may be critical in future therapeutic approaches for human diseases.